Antibiotic product, use and formulation thereof

ABSTRACT

An antibiotic product is comprised of at least three dosages forms, each of which has a different release profile, with the C max  for the antibiotic product being reached in less than about twelve hours. In one embodiment, there is an immediate release dosage form, as well as two or more sustained release dosage forms, with each of the dosage forms having a different release profile, wherein each reaches a C max  at different times.

This application claims the priority of U.S. Provisional ApplicationSer. No. 60/488,754, filed on Jul. 21, 2003, the disclosures of whichare hereby incorporated by reference in their entireties.

This invention relates to an antibiotic product, as well as the use andformulation thereof.

A wide variety of antibiotics have been used, and will be used, in orderto combat bacterial infection. In general, such antibiotics can beadministered by a repeated dosing of immediate release dosage forms,which results in poor compliance or as a controlled release formulation(slow release) at higher administered doses. The present invention isdirected to providing for an improved antibiotic product.

In accordance with one aspect of the present invention, there isprovided an antibiotic pharmaceutical product which is comprised of atleast two, preferably at least three, antibiotic dosage forms. Suchdosage forms are formulated so that each of the dosage forms has adifferent release profile.

In a particularly preferred embodiment, there are at least two,preferably at least three dosage forms, each of which has a differentrelease profile and the release profile of each of the dosage forms issuch that the first and second dosage forms each start release of theantibiotic contained therein at about the same time, and the thirddosage form starts release of the antibiotic contained therein at a timeafter the second dosage form starts release of antibiotic containedtherein.

In another particularly preferred embodiment, there are at least two,preferably at least three dosage forms, each of which has a differentrelease profile and the release profile of each of the dosage forms issuch that the dosage forms each start release of the antibioticcontained therein at different times after administration of theantibiotic product.

Thus, in accordance with an aspect of the present invention, there isprovided a single or unitary antibiotic product that has containedtherein at least two, preferably at least three antibiotic dosage forms,each of which has a different release profile, whereby the antibioticcontained in at least two of such dosage forms is released at differenttimes.

In general neither of the second or third dosage forms starts release ofantibiotic contained therein before the first dosage form starts releaseof antibiotic contained therein.

More particularly, in one aspect, the antibiotic product contains atleast three dosage forms, the first of which is an immediate releasedosage form, the second of which is a sustained release dosage form, andthe third of which is a sustained release dosage form, with the seconddosage form initiating release at about the same time as the firstdosage form or at a time after the first dosage form (the initiation ofsustained release is delayed for a period of time), with the thirddosage form initiating release after release is initiated from both thefirst and second dosage forms.

In accordance with a further aspect of the invention, the antibioticproduct may be comprised of at least four different dosage forms, atleast three of which starts to release the antibiotic contained thereinat different times after administration of the antibiotic product.

The antibiotic product generally does not include more than five dosageforms with different release times.

In accordance with a preferred embodiment, the antibiotic product has anoverall release profile such that when administered the maximum serumconcentration of the total antibiotic released from the product isreached in less than twelve hours, preferably in less than eleven hours.In an embodiment, the maximum serum concentration of the totalantibiotic released from the antibiotic product is achieved no earlierthan four hours after administration.

In accordance with one preferred embodiment of the invention, there areat least three dosage forms. One of the at least three dosage forms isan immediate release dosage form whereby initiation of release of theantibiotic therefrom is not substantially delayed after administrationof the antibiotic product. The second and third of the at least threedosage forms are sustained release dosage forms as those terms are knownin the art. Additionally, initiation of release of the antibiotic may besubstantially delayed after administration of the antibiotic productfrom each of the sustained release dosage forms and from each other,however, when release is initiated the second and third dosage fromsrelease antibioitc as sustained release dosage forms. The delay ofinitiation of release of each of the sustained release dosage forms, oronly one of them, may be accomplished for example by using a pHsensitive or a non-pH sensitive enteric coating, depending on the typeof antibiotic product, whereby the sustained release of the antibioticfrom the second and third dosage form is delayed until after initiationof release of the antibiotic from the immediate release dosage form.More particularly, the antibiotic released from the second of the atleast two dosage forms achieves a C_(max) (maximum serum concentrationin the serum) at a time after the antibiotic released from the first ofthe at least three dosage forms achieves a C_(max) in the serum, and theantibiotic released from the third dosage form achieves a C_(max) in theserum after the C_(max) of antibiotic released from the second dosageform.

In one embodiment the first and second of the at least two dosage formsinitiate their respective immediate and sustained releases of antibioticat about the same time.

In one embodiment the initiation of the sustained release of antibioticfrom the second of the at least two dosage forms is delayed until afterthe immediate release of antibiotic is initiated from the first dosageform.

In all embodiments comprising three or more dosage forms, the initiationof the sustained release of antibiotic from the third dosage form isdelayed until after the sustained release of antibiotic is initiatedfrom the second dosage form.

In one embodiment, the second of the at least two dosage forms initiatesrelease of the antibiotic contained therein at least one hour after thefirst dosage form, with the initiation of the release therefromgenerally occurring no more than six hours after initiation of releaseof antibiotic from the first dosage form of the at least three dosageforms.

In general, the immediate release dosage form produces a C_(max) for theantibiotic released therefrom within from about 0.5 to about 2 hours,with the second dosage form of the at least three dosage forms producinga C_(max) for the antibiotic released therefrom in no more than aboutfour hours. In general, the C_(max) for such second dosage form isachieved no earlier than two hours after administration of theantibiotic product; however, it is possible within the scope of theinvention to achieve C_(max) in a shorter period of time.

As hereinabove indicated, the antibiotic product may contain at leastthree or at least four or more different dosage forms. For example, ifthe antibiotic product includes a third dosage form, the antibioticreleased therefrom reaches a C_(max) at a time later than the C_(max) isachieved for the antibiotic released from each of the first and seconddosage forms. In a preferred embodiment, release of antibiotic from thethird dosage form is started after initiation of release of antibioticfrom both the first dosage form and the second dosage form. In oneembodiment, C_(max) for antibiotic release from the third dosage form isachieved within eight hours.

In another embodiment, the antibiotic product contains at least fourdosage forms, with each of the at least four dosage forms havingdifferent release profiles, whereby the antibiotic released from each ofthe at least four different dosage forms achieves a C_(max) at adifferent time.

As hereinabove indicated, in a preferred embodiment, irrespective ofwhether the antibiotic contains at least two or at least three or atleast four different dosage forms each with a different release profile,C_(max) for all the antibiotic released from the antibiotic product isachieved in less than twelve hours, and more generally is achieved inless than eleven hours.

As hereinabove indicated, in a particularly preferred embodiment,wherein the antibiotic product contains at least two or at least threeor at least four different dosage forms each with a different releaseprofile, C_(max) for antibiotic released from each of the individualdosage forms is achieved in less than twelve hours, and more generallyeach is achieved in less than eleven hours.

In a preferred embodiment, the antibiotic product is a once a dayproduct, whereby after administration of the antibiotic product, nofurther product is administered during the day; i.e., the preferredregimen is that the product is administered only once over a twenty-fourhour period. Thus, in accordance with the present invention, there is asingle administration of an antibiotic product with the antibiotic beingreleased in a manner such that overall antibiotic release is effectedwith different release profiles in a manner such that the overallC_(max) for the antibiotic product is reached in less than twelve hours.The term single administration means that the total antibioticadministered over a twenty-four hour period is administered at the sametime, which can be a single tablet or capsule or two or more thereof,provided that they are administered at essentially the same time.

Applicant has found that a single dosage antibiotic product comprised ofat least three antibiotic dosage forms each having a different releaseprofile is an improvement over a single dosage antibiotic productcomprised of an antibiotic dosage form having a single release profile.Each of the dosage forms of antibiotic in a pharmaceutically acceptablecarrier may have one or more antibiotics and each of the dosage formsmay have the same antibiotic or different antibiotics.

It is to be understood that when it is disclosed herein that a dosageform initiates release after another dosage form, such terminology meansthat the dosage form is designed and is intended to produce such laterinitiated release. It is known in the art, however, notwithstanding suchdesign and intent, some “leakage” of antibiotic may occur. Such“leakage” is not “release” as used herein.

If at least four dosage forms are used, the fourth of the at least fourdosage forms may be a sustained release dosage form or a delayed releasedosage form. If the fourth dosage form is a sustained release dosageform, even though C_(max) of the fourth dosage form of the at least fourdosage forms is reached after the C_(max) of each of the other dosageforms is reached, antibiotic release from such fourth dosage form may beinitiated prior to or after release from the second or third dosageform.

The antibiotic product of the present invention, as hereinabovedescribed, may be formulated for administration by a variety of routesof administration. For example, the antibiotic product may be formulatedin a way that is suitable for topical administration; administration inthe eye or the ear; rectal or vaginal administration; as nose drops; byinhalation; as an injectable; or for oral administration. In a preferredembodiment, the antibiotic product is formulated in a manner such thatit is suitable for oral administration.

For example, in formulating the antibiotic product for topicaladministration, such as by application to the skin, the at least twodifferent dosage forms, each of which contains an antibiotic, may beformulated for topical administration by including such dosage forms inan oil-in-water emulsion, or a water-in-oil emulsion. In such aformulation, the immediate release dosage form is in the continuousphase, and the sustained release dosage form is in a discontinuousphase. The formulation may also be produced in a manner for delivery ofthree dosage forms as hereinabove described. For example, there may beprovided an oil-in-water-in-oil emulsion, with oil being a continuousphase that contains the immediate release component, water dispersed inthe oil containing a first sustained release dosage form, and oildispersed in the water containing a third sustained release dosage form.

It is also within the scope of the invention to provide an antibioticproduct in the form of a patch, which includes antibiotic dosage formshaving different release profiles, as hereinabove described.

In addition, the antibiotic product may be formulated for use in the eyeor ear or nose, for example, as a liquid emulsion. For example, thedosage form may be coated with a hydrophobic polymer whereby a dosageform is in the oil phase of the emulsion, and a dosage form may becoated with hydrophilic polymer, whereby a dosage form is in the waterphase of the emulsion.

Furthermore, the antibiotic product with at least three different dosageforms with different release profiles may be formulated for rectal orvaginal administration, as known in the art. This may take the form of acream or emulsion, or other dissolvable dosage form similar to thoseused for topical administration.

As a further embodiment, the antibiotic product may be formulated foruse in inhalation therapy by coating the particles and micronizing theparticles for inhalation.

In a preferred embodiment, the antibiotic product is formulated in amanner suitable for oral administration. Thus, for example, for oraladministration, each of the dosage forms may be used as a pellet or aparticle, with a pellet or particle then being formed into a unitarypharmaceutical product, for example, in a capsule, or embedded in atablet, or suspended in a liquid for oral administration.

Alternatively, in formulating an oral delivery system, each of thedosage forms of the product may be formulated as a tablet, with each ofthe tablets being put into a capsule to produce a unitary antibioticproduct. Thus, for example, antibiotic products may include a firstdosage form in the form of a tablet that is an immediate release tablet,and may also include two or more additional tablets, each of whichprovides for a sustained release of the antibiotic, as hereinabovedescribed, whereby the C_(max) of the antibiotic released from each ofthe tablets is reached at different times, with the C_(max) of the totalantibiotic released from the antibiotic product being achieved in lessthan twelve hours.

The formulation of an antibiotic product including at least three dosageforms with different release profiles for different routes ofadministration is deemed to be within the skill of the art from theteachings herein. As known in the art, with respect to sustainedrelease, the time of release can be controlled by the concentration ofantibiotics in the coating and/or the thickness of the coating.

In accordance with the present invention, each of the dosage formscontains the same antibiotic; however, each of the dosage forms maycontain more than one antibiotic.

The Immediate Release Component

The immediate release portion of this system can be a mixture ofingredients that breaks down quickly after administration to release theantibiotic. This can take the form of either a discrete pellet orgranule that is mixed in with, or compressed with, the other threecomponents.

The materials to be added to the antibiotics for the immediate releasecomponent can be, but are not limited to, microcrystalline cellulose,corn starch, pregelatinized starch, potato starch, rice starch, sodiumcarboxymethyl starch, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose,chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linkedchitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol,sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose,polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol,Eudragit, etc.), polyethylene glycols, such as low molecular weight PEGs(PEG2000-10000) and high molecular weight PEGs (Polyox) with molecularweights above 20,000 daltons.

It may be useful to have these materials present in the range of 1.0 to60% (W/W). More preferably these materials are present in the range of3-40%. Most preferably these materials are present in the range of 5-20%so that the drug loading may be kept high and the overall dosage formsize is minimized.

In addition, it may be useful to have other ingredients in this systemto aid in the dissolution of the drug, or the breakdown of the componentafter ingestion or administration. These ingredients can be surfactants,such as sodium lauryl sulfate, sodium monoglycerate, sorbitanmonooleate, sorbitan monostearate, polyoxyethylene sorbitan monooleate,glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate,caprylocaproyl macrogol-8-glycerides, one of the non-ionic surfactantssuch as the Pluronic line of surfactants, or any other material withsurface active properties, or any combination of the above. The materialmay also be a disentegrant or superdisentegrant known to those in theart such as coscarmellose sodium, cross linked PVP, and others.

These materials may be present in the rate of 0.05-15% (W/W).

Sustained Release Component

The components in this composition are the same as the immediate releasecomponent, but with additional polymers integrated into the composition,or as coatings over the pellet or granule.

The kind of materials useful for this purpose can be, but are notlimited to,ethylcellulose,hydroxypropylmethylcellulose,hydroxypropylcellulose,hydroxyethylcellulose, carboxymethylcellulose, methylcellulose,nitrocellulose, Eudragit RS, and Eudragit RL, Carbopol, or polyethyleneglycols with molecular weights in excess of 8,000 daltons.

These materials can be present in concentrations from 4-20% (W/W).Preferably the amounts are just enough to provide the desired in vivorelease profile.

When it is desired to delay inititiation of release from either thefirst or the second of the sustained release dosage forms, anappropriate coating may be used to delay inititiation of the sutainedrelease, such as a pH sensitive or a non-pH sensitive coating.

The Non-pH Sensitive Coating for Sustained Release Dosage Form

Materials that can be used to obtain a delay in release suitable forthis component of the invention can be, but are not limited to,polyethylene glycol (PEG) with molecular weight above 4,000 daltons(Carbowax, Polyox), waxes such as white wax or bees wax, paraffin,acrylic acid derivatives (Eudragit RS), cellulose acetate, andethylcellulose.

Typically these materials can be present in the range of 0.5-25% (W/W)of this component. Preferably the materials are present in an amountjust enough to provide the desired in vivo lag time and T_(max).

The pH Sensitive Coating for Sustained Release Dosage Form

The kind of materials useful for this purpose can be, but are notlimited to, cellulose acetate pthalate, Eudragit L, Eudragit S, EudragitFS, and other pthalate salts of cellulose derivatives.

These materials can be present in concentrations from 4-20% (W/W) ormore. Preferably the materials are present in an amount just enough toprovide the desired in vivo lag time and T_(max).

As hereinabove indicated, the units comprising the antibioticcomposition of the present invention can be in the form of discretepellets or particles contained in the capsule, or particles embedded ina tablet or suspended in a liquid suspension.

The antibiotic composition of the present invention may be administered,for example, by any of the following routes of administration:sublingual, transmucosal, transdermal, parenteral, etc., and preferablyis administered orally. The composition includes a therapeuticallyeffective amount of the antibiotic, which amount will vary with theantibiotic to be used, the disease or infection to be treated, and thenumber of times that the composition is to be delivered in a day. Thecomposition is administered to a host in an amount effective fortreating a bacterial infection.

This system will be especially useful in extending the practialtherapeutic activity for antibiotics with elimination half lives of lessthan 20 hours and more particularly with elimination half-lives of lessthan 12 hours, and will be particularly useful for those drugs withhalf-lives of 2-10 hours. The following are examples of some antibioticswith half-lives of about 1 to 12 hours: Cefadroxil, cefazolin,cephalexin, cephalothin, cephapirin, cephacelor, cephprozil, cephadrine,cefamandole, cefonicid, ceforanide, cefuroxime, cefixime, cefoperazone,cefotaxime, cefpodoxime, ceftaxidime, ceftibuten, ceftizoxime,ceftriaxone, cefepime, cefmetazole, cefotetan, cefoxitin, loracarbef,imipenem, erythromycin (and erythromycin salts such as estolate,ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin,clarithromycoin, dirithromycin, troleanomycin, penicillin V, penicilinsalts, and complexes, methicillin, nafcillin, oxacillin, cloxacillin,dicloxacillin, amoxicillin, amoxicillin and clavulanate potassium,ampicillin, bacampicillin, carbenicillin indanyl sodium (and other saltsof carbenicillin) mezlocillin, piperacillin, piperacillin andtaxobactam, ticarcillin, ticarcillin and clavulanate potassium,clindamycin, vancomycin, novobiocin, aminosalicylic acid, capreomycin,cycloserine, ethambutol HCl and other salts, ethionamide, and isoniazid,ciprofloxacin, levofloxacin, lomefloxacin, nalidixic acid, norfloxacin,ofloxacin, sparfloxacin, sulfacytine, suflamerazine, sulfamethazine,sulfamethixole, sulfasalazine, sulfisoxazole, sulfapyrizine,sulfadiazine, sulfinethoxazole, sulfapyridine, metronidazole,methenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine,co-triamoxazole, pentamidine, and trimetrexate.

The invention will be further described with respect to the followingexamples; however, the scope of the invention is not limited thereby.All percentages in this specification, unless otherwise specified, areby weight.

EXAMPLES

I. Immediate Release Component

Formulate the composition by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a dry blend. If water or other solvent was used,dry the blend in a suitable pharmaceutical drier, such as a vacuum ovenor forced-air oven. The product may be sieved or granulated, andcompressed using a suitable tablet press, such as a rotary tablet press,or filled into a capsule or sachet with a suitable filler.

Ingredient Conc. (% W/W) Example 1: Amoxicillin 65% (W/W)Microcrystalline cellulose 20 Povidone 10 Croscarmellose sodium 5Example 2: Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Povidone10 Croscarmellose sodium 10 Example 3: Amoxicillin 65% (W/W)Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellosesodium 5 Example 4: Amoxicillin 75% (W/W) Polyethylene glycol 4000 10Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 5:Amoxicillin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5Example 6: Clarithromycin 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 7:Clarithromycin 75% (W/W) Microcrystalline cellulose 15Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 8:Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Hydroxypropylcellulose 5 Example 9: Clarithromycin 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 10:Ciprofloxacin 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 11:Ciprofloxacin 75% (W/W) Microcrystalline cellulose 15Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 12:Ciprofloxacin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene glycol2000 10 Hydroxypropylcellulose 5 Example 13: Cirpofloxacin 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 14:Ceftibuten 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Hydroxypropylcellulose 5 Example 15: Ceftibuten 75% (W/W)Polyethylene Glycol 4000 20 Polyvinylpyrrolidone 5II. Sustained Release Component

Examples 16-21 utilize film coating techniques commonly known to thoseskilled in the art to create the sustained release component by layeringof such sustained release polymers onto an active core. In general thesteps involve first making a coating dispersion or solution in organicor aqueous solvent. Second the coating is applied at the properconditions to produce an acceptably uniform film. This is done in asuitable coating apparatus such as a pan coater or a fluid bed wurstercolumn coater. Optionally the product may be further cured if necessary.Curing studies are recommended with sustained release membranes.

To create a matrix type sustained release component, formulate theingredients of examples 22-25 by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a hot melt process. If water or other solventwas used, dry the blend in a suitable pharmaceutical drier, such as avacuum oven or forced-air oven. Allow the product to cool.

The product produced by either manner may be sieved or granulated, andcompressed using a suitable tablet press, such as a rotary tablet press,or filled into capsules using a suitable capsule filler such as a MG2Futura.

Ingredient Conc. (% W/W) Example 16: Core from Example 1 75% (W/W)Ethylcellulose 20 HPC 5 Example 17: Core from Example 5 80% (W/W)Eudragit RS 10 Eudragit RL 5 Talc 3 TEC 2 Example 18: Core from Example5 90% (W/W) Ethylcellulose 9 Triacetin 1 Example 19: Core from Example 790% (W/W) Surelease 10 Example 20: Core from Example 11 85% (W/W)Kollicoat SR 10 TBC 5 Example 21: Core from Example 15 80% (W/W)Polyethylene glycol 8000 5 Eudgragit RS 30D 15 Example 22: Amoxicillin75% (W/W) Hydroxyethylcellulose 10 Polyethylene glycol 4000 10Hydroxypropylcellulose 5 Example 23: Ciprofloxacin 75% (W/W) Lactose 10Povidone (PVP) 10 Polyethylene glycol 2000 5 Example 24: Clarithromycin75% (W/W) Polyethylene glycol 4000 10 Povidone (PVP) 10Hydroxypropylcellulose 5 Example 25: Ceftibuten 75% (W/W) Lactose 15Polyethylene glycol 4000 5 Polyvinylpyrrolidone 5III. Sustained Release Dosage form with Coating to Delay Initiation ofSustained Release:

Delaying the initiation of the sustained release of antibiotic in thepresent invention is achieved by either coating the immediate releasecomponent bead with a sustained release coating and then subsequentlyapplying an enteric coating or non pH sensitive delayed release coatingto that coated bead, or alternatively the sustained release matrixcomponent bead may be coated with an enteric coating or non pH sensitivedelayed release coating.

Coatings can be applied to either the sustained release coated beads orthe sustained release matrix beads to form a product which pulses thetherapeutical agent in a desired environment or location of the GItract.

III A. The following examples describe the detailed preparation of thesustained-release coating materials to be applied to the immediaterelease beads from section I of the examples, resulting in a sustainedrelease component of the invention.

Example 26 Eudragit RS Example—Organic Coating

Component Percentage (%) Part A Eudragit RS-100 6.0 Triethyl Citrate 1.0Talc 0.5 Acetone 92.5

-   Step 1. Dissolve Eudragit in Acetone.-   Step 2. Mix TEC and talc in a separate container with some Acetone.-   Step 3. Add step 2 to Step 1, and allow to mix for 20 minutes before    spraying.

Example 27 SureleaseTM Example—Aqueous Coating

Component Percentage (%) Part A Surelease 90 Purified Water 10.0

-   Step 1. Mix surelease and water for 30 minutes before spraying.

Directions for application of the sustained release coating to thebeads:

-   Charge a wurster column equipped fluid bed with the beads to be    coated. Spray the coating onto the beads at a rate and temperature    known to those skilled in the art of bead coating so as to    efficiently coat the beads to give a weight gain of between 4 and    20%. Dry the beads to the specified level of coating solvent for    optimum handling and stability. Cure the beads for additional    congealing of the sustained release film if required.

III B. The following are examples of the pH sensitive, or entericrelease, coating that can be used to optionally delay the onset ofaction of any or all of the second, third, or additional dosage forms.

The composition of the aqueous Eudragit L30D-55 dispersion to be appliedto the immediate release components that have been treated with theabove-described sustained release coatings, or to the sustained-matrixpellets is provided below in Example 28.

Example 28 Eudragit® L 30 D-55 Aqueous Coating Dispersion

Component Percentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6Talc 8.0 Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9

Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

-   -   Step 1 Suspend triethyl citrate and talc in deionized water.    -   Step 2 The TEC/talc suspension is then homogenized using a        PowerGen 700 high shear mixer.    -   Step 3 Add the TEC/talc suspension slowly to the Eudragit® L 30        D-55 latex dispersion while stirring.    -   Step 4 Allow the coating dispersion to stir for one hour prior        to application onto the matrix pellets.

Example 29 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to thematrix pellets is provided below:

Eudragit® S 100 Aqueous Coating Dispersion

Component Percentage (%) Part A Eudragit ® S 100 12.0 1 N AmmoniumHydroxide 6.1 Triethyl Citrate 6.0 Purified Water 65.9 Part B Talc 2.0Purified Water 8.0 Solid Content 20.0 Polymer Content 12.0

Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part I:

-   -   (i) Dispense Eudragit® S 100 powder in deionized water with        stirring.    -   (ii) Add ammonium hydroxide solution drop-wise into the        dispersion with stirring.    -   (iii) Allow the partially neutralized dispersion to stir for 60        minutes.    -   (iv) Add triethyl citrate drop-wise into the dispersion with        stirring. Stir for about 2 hours prior to the addition of Part        B.

Part II:

-   -   (i) Disperse talc in the required amount of water    -   (ii) Homogenize the dispersion using a PowerGen 700D high shear        mixer.    -   (iii) Part B is then added slowly to the polymer dispersion in        Part A with a mild stirring.

Coating Conditions for the Application of Aqueous Coating Dispersions

The following coating parameters were used to coat matrix pellets witheach of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous filmcoating.

Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.8 Bar Pump Rate 2 gram per minute

-   -   (i) Coat matrix pellets with L30 D-55 dispersion such that you        apply 12% coat weight gain to the pellets.    -   (ii) Coat matrix pellets with S 100 dispersion such that you        apply 20% coat weight gain to the pellets.

III. C. The following examples describe the detailed preparation of thenon pH sensitive coating materials to be used to optionally delay theonset of action of any or all of the second, third, or additional dosageforms.

Example 30 Rupturable Film

Component Percentage (%) Part A Cellulose Acetate 398-10 6.0 PEG 400 1.5Acetone 92.5

-   Step 1. Dissolve cellulose acetate in Acetone.-   Step 2. Add TEC to Step 1, and allow to mix for 20 minutes.

Directions for application of the sustained release coating to thebeads:

-   Charge a wurster column equipped fluid bed with the beads to be    coated. The beads must contain a component which will swell rapidly    upon exposure to moisture. Beads containing croscarmellose sodium in    Section I are good candidates as are beads with swellable    hydrophilic polymers from Section II. Spray the coating onto the    beads at a rate and temperature known to those skilled in the art of    bead coating so as to efficiently coat the beads to give a weight    gain of between 4 and 20%. Dry the beads to the specified level of    coating solvent for optimum handling and stability.

Coating Conditions for the Application of the Rupturable Film Coating.

The following coating parameters were used to coat matrix mini tabletsfrom example 22 with the rupturable film coating. A 2.5% weight gainprovided the desired lag time.

Coating Equipment Vector LDCS Coating System with 1.3 L pan Spray nozzlediameter 0.8 mm Material Charge 800 grams Inlet Air Temperature 40 to45° C. Outlet Air Temperature 18 to 23° C. Atomization Air Pressure 25psi Pump Rate 6 grams per minute

The enteric coatings and non-pH sensitive coatings as described abovecan be applied to either a sustained release matrix bead as in examples16-25, or to the immediate release component beads that have beenpreviously treated with a sustained release coating, to thereby providea sustained release bead with a delayed onset of action. In addition,the enteric coating or non-pH sensitive coating can be applied to theimmediate release component bead directly to provide delayed onset ofaction.

IV. Final Composition

After all of the individual components are manufactured the final dosageform is assembled and may take the shape of a tablet, capsule or sachet.Preferably the final dosage form takes the shape of a capsule or tablet.Most preferably the final dosage form is a tablet.

The various dosage forms will combined in the final dosage form in aratio such that the Cmax is achieved in less than twelve hours and theproduct provides once a day coverage of anti-infective agent. Preferablythe first, second, and third dosage forms provide 20-70%, 10-70% and10-70% of the total dosage form, respectively. More preferably the ratioof first, second and third dosage forms are in the range of 25-66%,15-60% and 15-60% of the total dosage form respectively. Most preferablythe ratio of the first, second and third dosage forms are in the rangeof 33-60%, 25-50%, and 25-50% respectively.

The present invention is particularly advantageous in that there isprovided an antibiotic product which provides an improvement over twicea day administration of the antibiotic and an improvement over a once aday administration of the antibiotic.

Numerous modifications and variations of the present invention arepossible in light of the above teachings, and therefore, within thescope of the appended claims the invention may be practiced otherwisethan as particularly described.

What is claimed is:
 1. A once-a-day antibiotic product comprising:first, second, and third antibiotic dosage forms, each of saidantibiotic dosage forms comprising at least one antibiotic and apharmaceutically acceptable carrier, said first antibiotic dosage formbeing an immediate release dosage form, said second and third antibioticdosage forms being sustained release dosage forms, wherein theantibiotic released from the first dosage form reaches a Cmax withinfrom about 0.5 hours to about 2 hours after administration of theproduct, wherein said second dosage form initiates release of antibioticat about the same time as said first dosage form initiates release ofantibiotic, and wherein said third dosage form initiates release ofantibiotic after said second dosage form initiates release ofantibiotic, and Cmax of the total antibiotic released from saidantibiotic product is achieved in less than about 12 hours fromadministration and said once-a-day antibiotic product contains the totaldosage of the at least one antibiotic for a twenty-four hour period,wherein the product is an oral dosage form, wherein the antibioticreleased from the second dosage form reaches a Cmax after Cmax isreached for the antibiotic released from the first dosage form, andwherein the first dosage form contains about 20-70% of the total dosageof antibiotic, the second dosage form contains about 10-70% of the totaldosage of antibiotic, and the third dosage form contains about 10-70% ofthe total dosage of antibiotic.
 2. The product of claim 1, wherein theCmax for the product is reached no earlier than four hours afteradministration.
 3. The product of claim 1, wherein the antibioticreleased from the third dosage form reaches a Cmax after Cmax is reachedfor the antibiotic released from the second dosage form.
 4. The productof claim
 1. wherein the first dosage form contains about 25-66% of thetotal dosage of antibiotic, the second dosage form contains about 15-60%of the total dosage of antibiotic, and the third dosage form containsabout 15-60% of the total dosage of antibiotic.
 5. The product of claim1 further comprising a fourth antibiotic dosage form, said fourthantibiotic dosage form being either a sustained or a delayed releasedosage form and comprising at least one antibiotic and apharmaceutically acceptable carrier and wherein said at least oneantibiotic released from said fourth antibiotic dosage form reaches aCmax after Cmax is achieved for antibiotic released from each of saidfirst, second, and third dosage forms.
 6. A process for treating abacterial infection in a host comprising: administering to a host theantibiotic product of claim 1, once-a-day.
 7. A process for treating abacterial infection in a host comprising: administering to a host theantibiotic product of claim 2, once-a-day,
 8. A process for treating abacterial infection in a host comprising: administering to a host theantibiotic product of claim 3, once-a-day.
 9. A process for treating abacterial infection in a host comprising: administering to a host theantibiotic product of claim 4, once-a-day.
 10. A process for treating abacterial infection in a host comprising: administering to a host theantibiotic product of claim 5, once-a-day.
 11. The product of claim 1,wherein said at least one antibiotic is amoxicillin.
 12. A process fortreating a bacterial infection in a host comprising administering to ahost the antibiotic product of claim 11, once-a-clay.
 13. The product ofclaim 5, wherein the Cmax for the product is reached no earlier thanfour hours after administration.
 14. The product of claim 5, wherein theantibiotic released from the second dosage form reaches a Cmax in nomore than about 4 hours after administration of the product.
 15. Theproduct of claim 12, wherein the antibiotic released from the thirddosage form reaches a Cmax after Cmax is reached for the antibioticreleased from the second dosage form.
 16. The product of claim 1,wherein said at least one antibiotic is cephalexin.
 17. A process fortreating a bacterial infection in a host comprising: administering to ahost the antibiotic product of claim 16, once-a-day.